Gene With A Thousand Faces

Can a single human gene be responsible for some forms of human obesity and mental retardation, not to mention mood disorders and, possibly, the brain devastation seen in Huntington’s and Fragile X diseases?

Baoji Xu, Ph.D., thinks so, and has authored numerous scientific publications that explain why. His latest, which appeared online March 18th on Nature Medicine’s website, revealed how this gene—brain-derived neurotrophic factor (Bdnf) gene—is responsible for a voracious and uncontrollable appetite in mice that leads to obesity.

Xu, an associate professor of pharmacology and physiology at Georgetown, revealed how a mutation in the Bdnf gene does not allow neurons to effectively pass along appetite suppressing signals from the body to the right place in the brain.

In humans, the leptin and insulin hormones are released in the body after a person eats to “tell” the body to stop feeding itself. But if the signals fail to reach correct locations in the hypothalamus, the area in the brain that signals satiety, the desire to eat continues.

“This is the first time protein synthesis in dendrites—the tree-like extensions of neurons—has been found to be critical for control of weight,” says Xu. “This discovery may open up novel strategies to help the brain control body mass.”

Ensuring neurons communicate

Xu has long investigated the Bdnf gene.

He became interested in it when, after receiving his Ph.D. in biological sciences from Stanford University in 1995, he went for postdoctoral training to the University of California, San Francisco. There, he took on the task of trying to describe what it is, exactly, that BDNF (the protein produced by the Bdnf gene) is doing in the brain. At the time, scientists knew it played key roles in the initial development of the peripheral nervous system, and that it was still widely expressed in the adult brain. But scientists had a difficult time studying it. When the gene was deleted in mice, the animals all died, perhaps due to problems in their peripheral nervous system.

Xu tried a technique in which he selectively deleted a different gene (TrkB) that produces the receptor that binds on to the BDNF protein produced by the Bdnf gene ⎯ essentially creating a backdoor approach to eliminating the brain’s use of BDNF. It worked. Now he had mice that did not use BDNF, and he has since employed the same technique to delete Bdnf or TrkB genes in specific brain regions in order to understand the complex and varied roles the gene plays in neurons. Xu also generated a mouse mutant in which TrkB gene expression is reduced to a quarter of the normal amount. He continued to use those models after coming to Georgetown in 2003 to conduct research in pharmacology and physiology.

Through these experiments, Xu and his colleagues have found that the gene produces a growth factor that makes neurons grow, and so it controls communication of all sorts between neurons. It is also vital to initial development of the brain.

For example, he has shown that during brain development after birth, Bdnf is important to the formation and maturation of synapses, the structures that permit neurons to send signals between them. The Bdnf gene generates one short transcript and one long transcript. Xu discovered that when the long-form Bdnf transcript is absent, the BDNF protein growth factor produced by the Bdnf gene is only synthesized in the cell body of a neuron, but not in its dendrites. The neuron then produces too many immature synapses, resulting in faulty communication and deficits in learning and memory in mice.

In the course of his research, Xu also found that the mice with the same Bdnf mutation grew to be severely obese.

Other researchers also began to look at the Bdnf gene in humans, and large-scale genome-wide association studies showed Bdnf gene variants are, in fact, linked to obesity.

Necessary for neural plasticity

Until Xu’s Nature Medicine study, no one has been able to describe exactly how BDNF controls body weight.

He and his team are now testing whether the obesity effects produced by BDNF can be reversed or even prevented. “I hope that we will eventually find a small-molecular compound that can stimulate BDNF synthesis in neuronal dendrites for the treatment of obesity,” Xu says.

At the same time, Xu is researching the role of BDNF in “synaptic plasticity”—the as-needed strengthening of synaptic connections that underlies memory and learning.

“If BDNF is deleted in an animal’s brain, the animal will struggle to learn new tasks,” Xu says. That major finding was published in Cell in 2008.

Mice harboring mutations in the Bdnf gene also exhibit other problems, such as high anxiety and mood disorders. “It is believed that anti-depressants work in part by up-regulating Bdnf gene expression,” he says.

Xu has also looked at brain disorders such as Huntington’s disease, and found that reduced levels of BDNF in the brain, which he suspects plays a crucial role in the manner in which this disease develops. In a 2010 study published in the Journal of Neuroscience, Xu reported that ramping up expression of BDNF in mice with Huntington’s disease reduced many of the overt symptoms of the disease.

Fragile X Syndrome, the most common form of inherited mental retardation, may also be related to malfunction of the gene, Xu says. “At a certain stage of development, maturation of dendritic spines is frozen. For example, in Fragile X Syndrome, there are too many immature dendritic spines,” he says.

“What we see in our mutant mouse and in Fragile X is similar,” Xu says. “If we could find a way to increase BDNF synthesis in dendrites, it may be helpful to people with this form of inherited mental retardation.”

He envisions a day when it might be possible to use a mimic of BDNF to treat the powerful disorders associated, in one way or the other, with the gene—work he has already begun. But Xu knows he is in the early days of discovery. “No matter how valuable it may turn out to be, none of this research is simple or easy,” he says. “But it is immensely exciting, and in my mind, really promising.”

By Renee Twombly, GUMC Communications
(Published March 23, 2012)